Many clinical and experimental tumors express tumor antigens that can be recognized by CTL infiltrates. Numerous lines of evidence indicate that tumor-infiltrating CTLs can be activated and expanded by appropriate vaccination. However, despite T-cell recognition, most antigenic tumors are not rejected in the host. The mechanisms that disable CTL-mediated tumor rejection include low immunogenicity of the tumors such as MHC down-regulation and weak TCR-MHC-peptide interaction, active suppression of T-cell responsiveness by tumor itself, including tumor-derived transforming growth factor-beta (TGF-beta) and soluble MHC class-I-related molecules (MIC), prevention of T cell infiltration by tumor barrier composed of infiltrating stroma, as well as immunoregulatory mechanisms of the host immune system, such as suppression by CTLA-4, CD4+CD25+ regulatory T cells, and IL13 produced by CD4+ NK T cells. In addition, ample evidence also indicates that lack of appropriate recognition of tumor cells by tumor-specific CTLs in both priming and effector phases can contribute to the silence of an anti-tumor immune response.
Signals for productive T-cell responses: The two signal theory
Two signals are required for T cells to respond to antigens presented by antigen-presenting cells (APCs) or target cells such as tumor cells. Engagement of the T-cell antigen receptor (TCR) with antigen (peptide-MHC complexes) provides the initial signal. The second signal, termed costimulation, is initiated by interaction between co-receptors such as CD28 on T cells and the corresponding ligands such as B7s expressed by APCs. While stimulation of T cells by the professional APCs bearing both antigen and costimulatory ligands leads to T-cell proliferation and cytokine production, engagement of the TCR with antigens in the absence of costimulation results in T-cell unresponsiveness, a state termed anergy. One major obstacle in tumor immune surveillance is that most tumor cells do not express co-stimulatory ligands, such as B7s. Therefore, T cells that recognize these tumor cells usually cannot be fully activated and develop into effector cells, resulting in the failure of host immune surveillance against these tumors.
Modulation of TCR and Costimulatory Signals May Reverse the Silent State of Tumor-specific Cytotoxic-T Cells
Immune responses against immunogenic tumors are primarily mediated by T cells including CD8+ CTLs and CD4+ helper T cells. The tumor mass often has large numbers of CTL infiltrates. However, these CTLs are mostly non-responsive to tumors, as they are unable to exert the cytotoxicity to tumor burdens. Experiments have shown that in vitro priming of these infiltrates through TCR in the presence of exogenous IL-2 could activate these cells to proliferate and develop into CTL effectors. However, when these CTLs are adoptively transferred into tumor-bearing animals, they often fail to eradicate the established tumors, unless an appropriate vaccine, which alters the avidity between the TCR and MHC-peptide complex, as well as a large quantity of interleukin-2 (IL-2) are administrated simultaneously, indicating that the enhanced TCR signaling is essential to overcome the non responsiveness of tumor specific CTLs. Additionally, it has been shown that enforced expression of B7 on tumor cells can induce strong CTL responses, which eventually results in eradication of the inoculated tumors. An effective tumor rejection has also been achieved when other costimulatory signaling pathways, such as ICOS (inducible costimulatory molecule), are activated by the corresponding-ligand B7HH/B7RP-expressing tumor cells. Thus, modulation of TCR and costimulatory signals can be a potentially powerful therapeutic approach against cancer.
Although enforced expression of costimulatory ligands in tumor cells may induce strong CTL response against the antigen-expressing tumors, application of this approach in clinic therapy is hampered by the lack of efficient tool to deliver the costimulatory molecules specifically into tumor cells in vivo. An alternative approach to induce tumor-specific CTL responses is to use professional APCs such as dendritic cells to present tumor antigens. However, one limitation of this approach is that tumors of weak immunogenicity, which are less susceptible to the effector function of CTLs, may need costimulatory signals to augment CTL function. In addition, since professional APCs may present self-antigens to a broad spectrum of T cells, adoptive transfer of tumor antigen-loaded professional APCs might result in development of systemic autoimmune diseases. Tumor immunotherapy is a promising approach that in a number of experimental animal models, as well as in some clinical trials, leads to the regression of established primary and metastatic cancer. However, currently available approaches remain less successful than desired. A major obstacle that has yet to be overcome derives from the observation that generation of effective CTL responses against antigenic tumors requires costimulatory signals, and that many tumors do not express the necessary costimulatory ligands. As a result, T cells recognizing these tumors are often non-responsive in vivo.
Immune responses against immunogenic tumors are mediated by CD8+-cytotoxic T lymphocytes (CTLs). Despite T cell recognition, most tumors are not rejected in the host. The mechanisms that may prevent CTL-mediated tumor rejection include inhibition of T-cell responsiveness by tumor-derived factors, such as transforming growth factor-β (TGF-β) and soluble MHC class-I-related molecules secreted by tumor cells, as well as negative regulation of the host immune system, including suppressive CTLA-4 signaling, the effect of CD25+ regulatory T cells, and suppression by IL-13 produced by CD4+ NK T cells. In addition to these mechanisms of active suppression, lack of effective recognition of tumors by T cells may disable an anti-tumor immune response, for example in the absence of TCR and/or costimulatory signals. Thus there remains a need for identifying agents and methods that allow and/or enhance anti-tumor immune responses in the absence of co-stimulatory signals.